Due to the drug resistance and side effects of currently used modalities of anti-HIV agents, new drug discovery in search of less toxic and non-cross resistant drugs with existing anti-HIV agents are critically needed. There is a great concern that a number of HIV patients under HAART fail to respond to the current available drugs. Thus, Patients need additional drugs for salvage therapy. Previously, under the support of this grant we have discovered several clinical candidates for HIV (DAPD; Amdoxovir) and cancer (L-OddC; Troxicitabine). Particularly, DAPD is quite promising for the treatment of HIV infection in that it lowered a significant viral load (1.9 log) in patients during Phase Lm clinical studies who fail the combination therapy. Thus, DAPD may be potentially useful for salvage therapy to patients who fail HAART and additional Phase II studies for DAPD are currently in progress. In order to discover novel anti-HIV nucleosides with unique resistance profiles, during the current funding period we have been synthesizing a various classes of compounds. From these efforts we have developed several elegant synthetic methodology for future structure-activity studies, and furthermore we discovered several novel classes of biologically promising compounds, including the D- & L-2'- or 3'-F-substituted 2',3'-unsaturated nucleosides. During the next funding cycle, we propose to scale-up those compounds which demonstrated promising anti-HIV activity in vitro and to pursue in-depth biological studies to assess the full potential of those compounds as clinical candidates, as our group has previously conducted for other compounds discovered in our laboratories, such as DAPD. In view of the interesting chemistry and biological activity, in this application we will continue to focus on the synthesis of 2'- or 3 '-F substituted unsaturated nucleosides for comprehensive structure-activity studies, which include: 1) Synthesis of D- & L-3'-F-2',3'-unsaturated nucleosides (3'-F-d4N, Class 11), 2) Synthesis of D- & L-2'-F-2',3'-unsaturated 4'-S-nucleosides (2'-F-Sd4N7 Class III), 3) Synthesis of D- & L-3'-F-2',3'- unsaturated 4'-S-nucleosides (3'-F-S-d4N7 Class N) 4) Enantiomeric synthesis of D- & L-2'-F-2',3'-unsaturated carbocyclic nucleosides (2'-F-C-d4N7 Class V), 5) Enantiomeric synthesis of D- & L-3 '-F-2',3'-unsaturated carbocyclic nucleosides (3 '-F-C-d4N, Class VI) molecular modeling studies. Recently, we have studied molecular mechanism of nucleoside drug resistance and discovered that there is a qualitative correlation between the relative binding energy and the anti-HIV activity. This is the first such studies demonstrating the potential of this molecular modeling approach.